The Colon and Drug Delivery

The importance of the colon varies in mammals according to the nature of their diet. Thus true carnivores have a short colon with a small caecum, whereas large ruminants have a high capacity rumen for fermentation. The appendix in humans is vestigial and apparently unimportant in the human nutritional process. On opening the abdomen, the large colon is usually easily visible because the transverse loop has a very antral position in the abdominal cavity and may contain gas. Figure 2.13 illustrates the main physiological features of the colon. The bacterial fermentation of ingested soluble carbohydrates yields carbon dioxide, and in some individuals if the redox potential is low enough, hydrogen and methane.

Compared to the small intestine it is shorter - 1.5 m rather than 5 m - and the lumen is wider, without the extra surface area provided by the folds of Kekring and the villi. The absorptive capacity for drugs is therefore markedly reduced but this can be balanced by the long periods of residence in the ascending colon. The major regions of the colon are the right or ascending colon; the transverse colon which is folded in front of the ascending and descending arms by the hepatic and splenic flexures; the descending colon which stores feces and finally the rectum and anus. Overall the length of the human colon is approximately 150 cm, but only the last

3. Transverse colon: Periodically filled with gas. pH 6-8 Residence time 0.2 to 4h, dependent on presence of stool Dispersion inhibited by forward propulsive waves by retrograde movements

3. Transverse colon: Periodically filled with gas. pH 6-8 Residence time 0.2 to 4h, dependent on presence of stool Dispersion inhibited by forward propulsive waves by retrograde movements

4. Descending and Sigmoid Colon Periodically filled with faeces Residence time 5h to 72h dependent on bowel habit

1. Ileocaecal Junction. pH 6-8.4 Periodic High dispersive forces Propulsion linked to gastric emptying Stagnation common, causing bunching of swallowed label

2. Ascending Colon -Caecal Region Periodically filled with liquid, moving in concert with gastric emptying

Residence Time 3-5h pH 5-8, dependent on fermentation. Stirred by movement of material across ileocae-cal valve: 7-10 litres per day

4. Descending and Sigmoid Colon Periodically filled with faeces Residence time 5h to 72h dependent on bowel habit

1. Ileocaecal Junction. pH 6-8.4 Periodic High dispersive forces Propulsion linked to gastric emptying Stagnation common, causing bunching of swallowed label

Fig. 2.13 Schematic of colon transit. From [25]

30 cm is accessible from the anus, since the folding of the splenic flexure resists material entering the transverse colon if rectal delivery of large volume enemas is attempted. Targeting the first half of the colon is therefore difficult from a physiological perspective; however, the bacterial population provides a step change in luminal environment with a different set of metabolic enzymes to aid selective release. As an incentive, drug delivery to the colon has often been an attractive goal for peptide delivery as it is supposed that the lack of digestive enzymes would facilitate absorption. A drawback is the lack of fluid for dissolution and the environment is moist rather than full of fluid, with normal maximal water content of 30 ml recoverable postmeal from the caecum [26]. When empty, the colon is collapsed with little motility but the transverse section may extend with gas following fermentation of the carbohydrate. The terminal segments may be occupied by stool and little drug absorption can occur from the distal regions under these conditions.

The wall of the ascending colon when scraped with a pH electrode gives an alkaline reading as high as pH 8, caused by secretion of bicarbonate by a sodium-dependent bicarbonate secretion which is non-chloride ion dependent [27]. This secretion of the bicarbonate would be expected to render the colon alkaline, but this is balanced by the bacterial fermentation of carbohydrate to short chain fatty acids, particularly in the caecum and right colon. Studies with reliable pH electrodes implanted on the colon wall during colonoscopy in areas free of debris indicate that patients with a normal bowel have a more acidic right colon (pH 7.05 ± 0.32), followed by a more alkaline transverse colon (pH 7.42 ± 0.51), becoming more acid moving towards the rectum (pH 7.15 ± 0.44). The lumen pH mirrors the changes of the wall, but remains consistently more acidic [28]. Press and colleagues (1998) report values illustrated in Fig. 2.12 [28, 29].

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